Hypothalamic-pituitary-adrenal axis activity in post-traumatic stress disorder and cocaine use disorder

Post-traumatic stress disorder (PTSD) is often comorbid with cocaine use disorder (CUD), but little is known about hypothalamic-pituitary-adrenal (HPA) axis function in PTSD + CUD. Here we review the clinical and pre-clinical literature of PTSD and CUD with the goal of generating hypotheses about HPA axis activity in comorbid PTSD + CUD. Low glucocorticoid (CORT) levels immediately after trauma exposure are associated with PTSD. CORT administered within 12 h of trauma exposure reduces later PTSD symptoms. Weeks-years after trauma, meta-analyses find lower CORT levels in patients with PTSD relative to never-traumatized controls; the same is found in a pre-clinical model of PTSD. In rodents, reduced basal CORT levels are consistently found after chronic cocaine self-administration. Conversely, increased CORT levels are found in CUD patients during the first 2 weeks of cocaine abstinence. There is evidence for CORT hyper-suppression after dexamethasone, high glucocorticoid receptor (GR) number pre-trauma, and increased GR translocation to the nucleus in PTSD. Hyper-suppression of HPA axis activity after dexamethasone suggests that PTSD individuals may have increased anterior pituitary GR. Given evidence for decreased anterior pituitary GR in rats that self-administer cocaine, PTSD + CUD individuals may have normal GR density and low basal CORT levels during late abstinence. Future studies should aim to reconcile the differences in pre-clinical and clinical basal CORT levels during cocaine and assess HPA axis function in both rodent models of CUD that consider stress-susceptibility and in PTSD + CUD individuals. Although additional studies are necessary, individuals with PTSD + CUD may benefit from behavioral and psychopharmacological treatments to normalize HPA axis activity. LAY SUMMARY Post-traumatic stress disorder (PTSD) is often comorbid with cocaine use disorder (CUD), but little is known about the hypothalamic-pituitary-adrenal (HPA) axis function in PTSD + CUD. The current review provides a synthesis of available clinical and pre-clinical data on PTSD and CUD with the goal of generating hypotheses about HPA axis activity in comorbid PTSD + CUD. While this review finds ample evidence supporting aberrant HPA axis activity in both PTSD and CUD, it suggests that more research is needed to understand the unique changes HPA axis activity in PTSD + CUD, as well as the bidirectional relationship between stress-susceptibility and motivation to seek cocaine.